Cefditoren pivoxil granular preparation and preparation method thereof

Abstract

The invention discloses a cefditoren pivoxil granular preparation and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. Comprising the following raw materials in parts by weight: 50-60 parts of a cefditoren pivoxil self-microemulsion drug delivery system, 30-50 parts of a filling agent, 0.5-3 parts of a disintegrating agent, 0.1-2 parts of an adhesive, 1-7 parts of a sweetening agent, 0.1-2 parts of a flavoring agent, 0.1-2 parts of a thickening agent and 0.01-0.05 part of an aromatic. According to the invention, a novel oral administration system, namely a self-emulsifying administration system, is adopted, so that the problem of dissolvability of an indissolvable drug, namely the cefditoren pivoxil, can be well solved, and the prepared cefditoren pivoxil granules have good dissolution release rate and are affirmative in the aspect of improving the oral bioavailability of the drug. In addition, the prepared cefditoren pivoxil particles are uniform in particle size distribution and good in taste, content, content uniformity and preparation stability.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and relates to a cefditoren pivoxil granule preparation and a preparation method thereof. BACKGROUND

[0002] Cefditoren pivoxil granules are developed by Japan Meiji Seika Kaisha, Ltd., and were first approved for marketing in Japan in April 1994, and are commercially available under the trade name MEIACT. Cefditoren pivoxil was approved for marketing in China in 2015. Cefditoren pivoxil belongs to the third generation of cephalosporins, and is metabolized into cefditoren in the intestinal wall and liver after absorption to exert antibacterial activity. The mechanism of action is to inhibit the synthesis of bacterial cell walls, and to play a bactericidal role by binding to various bacterial penicillin binding proteins. Cefditoren pivoxil has strong antibacterial activity against gram-positive bacteria (such as Staphylococcus, Streptococcus, etc.) and gram-negative bacteria (such as Escherichia coli, Haemophilus influenzae, etc.). It is used to treat skin infections, perianal abscesses, otitis media, sinusitis, pharyngolaryngitis, tonsillitis, pneumonia, acute and chronic bronchitis, and the like caused by sensitive bacteria.

[0003] Cefditoren pivoxil is a light yellowish white to light yellow crystalline powder, and has a chemical name of 2,2-dimethylpropionyloxymethyl (6R,7R)-7-{(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetylamino}-3-{(Z)-2-(4-methyl-1,3-thiazol-5-yl)vinyl}-8-oxo-5-thia-1-azabicyclo{4.2.0}oct-2-ene-2-carboxylate, a molecular formula of C 25 H 28 N6O7S3, and a molecular weight of 620.72. The structural formula is as follows:

[0004]

[0005] Cefditoren pivoxil belongs to the class II drug in the biopharmaceutics classification system, and the patents CN97199098.0 and CN99802785.5 indicate that cefditoren pivoxil has two forms of orthorhombic crystal form and amorphous form. The crystalline cefditoren pivoxil has high purity, high thermal stability and high humidity stability, but it is not suitable for oral use due to its poor water solubility. Due to its high stability, the currently marketed raw material is a crystalline compound, and the solid preparation on the market uses an amorphous compound as an active ingredient, so the raw material needs to be converted into an amorphous form in the preparation process to improve its solubility before preparation of the preparation. The preparation method has the defects of difficult preparation process, poor stability of the amorphous cefditoren pivoxil and the preparation. The patent CN117883391A involves a technical solution in which the crystalline cefditoren pivoxil is dissolved in a mixed solution of N,N-dimethylformamide and ethanol, and then added to a high-molecular cellulose aqueous solution. A precipitate is separated out during the addition process, collected by filtration, washed, dried under reduced pressure, and then an amorphous cefditoren pivoxil composition is obtained. The preparation method has the defects of complex preparation process and poor stability of the amorphous cefditoren pivoxil. Low-temperature control is required during the preparation of the amorphous cefditoren pivoxil, and high temperature and moisture during the drying process will cause uncontrollable impurity growth. In addition, the use of chemical reagents can cause residues, affecting the quality of the product. The storage conditions of the amorphous cefditoren pivoxil are relatively high, and there is a risk of crystal type rotation during storage and preparation of the preparation.

[0006] Therefore, how to develop a cefditoren pivoxil granular preparation with good taste, particle size distribution, dissolution release rate and stability, simple preparation method, good process reproducibility and scalable production, and a preparation method thereof are technical problems that those skilled in the art need to solve. SUMMARY

[0007] Therefore, the present application provides a cefditoren pivoxil granular preparation and a preparation method thereof.

[0008] In order to achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0009] A cefditoren pivoxil granular preparation comprises the following raw materials by weight: cefditoren pivoxil self-microemulsion drug delivery system 50-60 parts, filler 30-50 parts, disintegrant 0.5-3 parts, binder 0.1-2 parts, sweetener 1-7 parts, flavoring agent 0.1-2 parts, thickening agent 0.1-2 parts, and fragrance 0.01-0.05 parts.

[0010] The cefditoren pivoxil self-microemulsion drug delivery system comprises a cefditoren pivoxil self-microemulsion drug delivery system solution and a solid carrier, and the mass ratio of the cefditoren pivoxil self-microemulsion drug delivery system solution to the solid carrier is (1-10):1.

[0011] The cefditoren pivoxil self-microemulsifying drug delivery system solution comprises cefditoren pivoxil and a blank self-microemulsifying drug delivery system solution, and the mass ratio of cefditoren pivoxil to the blank self-microemulsifying drug delivery system solution is 1:(2-10);

[0012] The blank self-microemulsifying drug delivery system solution comprises an oil phase, an emulsifier and a co-emulsifier, the mass ratio of the emulsifier to the co-emulsifier is (1-5):(1-5), and the weight ratio of the oil phase to the mixture of the emulsifier and the co-emulsifier is (1-5):(1-5).

[0013] Further, the oil phase is one or a mixture of several of monoglyceride oleate, monoglyceride linoleate, ethyl oleate or hydrogenated vegetable oil; preferably monoglyceride linoleate;

[0014] The emulsifier is one or a mixture of several of fatty acid sorbitan, Tween 80, sodium dodecyl sulfate or Span 80; preferably Tween 80;

[0015] The co-emulsifier is one or a mixture of several of ethanol, butanol, glycerol, diethylene glycol monoethyl ether or polyethylene glycol 400; preferably diethylene glycol monoethyl ether;

[0016] The solid carrier is one or a mixture of several of sucrose, mannitol, lactose, glucose or trehalose; preferably lactose.

[0017] Further, the filler is one or a mixture of several of microcrystalline cellulose, sucrose, lactose or mannitol; preferably sucrose;

[0018] The disintegrant is one or a mixture of several of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked povidone or cross-linked sodium carboxymethyl cellulose; preferably sodium carboxymethyl starch;

[0019] The binder is one or a mixture of several of hypromellose, povidone or hydroxypropyl cellulose; preferably povidone K25;

[0020] The sweetener is one or a mixture of several of aspartame, sucralose or sodium saccharin; preferably sucralose;

[0021] The flavoring agent is one or a mixture of several of sodium chloride, β-cyclodextrin, ion exchange resin or chitosan; preferably sodium chloride;

[0022] The thickening agent is one or a mixture of several of sodium carboxymethyl cellulose, polyoxyethylene, dextrin, gelatin or gum arabic; preferably dextrin;

[0023] The fragrance is one of vanillin, ethyl vanillin, strawberry flavor or cherry flavor or a mixture of several thereof; preferably strawberry flavor.

[0024] The present application also provides a preparation method of cefditoren pivoxil granule preparation, comprising the following steps:

[0025] (1) According to the cefditoren pivoxil granule preparation, each raw material is weighed;

[0026] (2) Preparation of blank self-microemulsion drug delivery system solution: the oil phase, emulsifier and co-emulsifier are mixed and stirred to obtain a blank self-microemulsion drug delivery system solution;

[0027] (3) Preparation of cefditoren pivoxil self-microemulsion drug delivery system solution: cefditoren pivoxil is added to the blank self-microemulsion drug delivery system solution obtained in step (2), and homogenized by a homogenizing emulsifier to obtain a cefditoren pivoxil self-microemulsion drug delivery system solution;

[0028] (4) Preparation of cefditoren pivoxil self-microemulsion drug delivery system: the solid carrier is dissolved in water to obtain a solid carrier solution, and the cefditoren pivoxil self-microemulsion drug delivery system solution obtained in step (3) is slowly added to the solid carrier solution, and homogenized by a homogenizing emulsifier, ultrasonic, freeze-dried to obtain a cefditoren pivoxil self-microemulsion drug delivery system;

[0029] (5) The binder is dissolved in water to obtain a binder solution, and the flavoring agent is added to the binder solution to disperse to obtain a mixed solution;

[0030] (6) The cefditoren pivoxil self-microemulsion drug delivery system obtained in step (4), the filler, the disintegrant, the sweetener and the thickening agent are pre-mixed in a wet granulator to obtain a pre-mixed product;

[0031] (7) The obtained pre-mixed product is transferred to a centrifugal granulator, the mixed solution obtained in step (5) is sprayed, water is used as a wetting agent for granulation, dried, the moisture content of the granules is controlled to be less than 1.5%, sieved, and the granules with a particle size greater than 850 μm are discarded, the sieved granules are transferred to a mixer, and the fragrance is added and mixed to obtain the cefditoren pivoxil granule preparation.

[0032] Further, in step (2), the stirring speed is 100-400 rpm, and the stirring time is 0.5-2 h.

[0033] Further, in step (3), the homogenization speed is 800-10000 rpm, and the homogenization time is 0.5-2 h.

[0034] Further, in step (4), the mass fraction of the solid carrier in the solid carrier solution is 2%-12%; the feeding speed of the cefditoren pivoxil self-microemulsion drug delivery system solution into the solid carrier solution is 5%-20% / min, based on the total mass of the cefditoren pivoxil self-microemulsion drug delivery system solution being 100%; the homogenization speed is 800-10000 rpm, and the homogenization time is 0.5-2 h; the ultrasonic power is 100-300 W, and the ultrasonic time is 10-30 min; the temperature of the freeze-drying is-40℃±10℃, and the freeze-drying time is 12-36 h.

[0035] Further, in step (5), the mass fraction of the binder in the binder solution is 4%-8%.

[0036] Further, in step (6), the rotating speed of the wet granulator is 110-300 rpm, the cutting rotating speed is 1000-2100 rpm, and the premixing time is 5-10 min.

[0037] Further, in step (7), the atomization pressure of the centrifugal granulator is 0.1-0.5 MPa, the main machine rotating speed is 8000-15000 rpm, the spraying pump rotating speed is 10-30 rpm, the granulation time is 0.5-1.5 min, the mixing machine rotating speed is 10-15 rpm, and the mixing time is 3-8 min.

[0038] The present application has the following beneficial effects: the self-microemulsion drug delivery system is an effective means for improving the solubility and oral bioavailability of poorly soluble drugs, the materials required for preparing the self-microemulsion drug delivery system can all be selected from pharmaceutically acceptable excipients, a solid carrier is selected to solidify the liquid self-microemulsion drug delivery system, which is convenient for storage and transportation and improves the bitterness of the drug to a certain extent, the solid self-microemulsion drug delivery system is obtained by freeze-drying, which avoids the decomposition of the drug, the decrease of potency or the generation of degradation caused by high temperature, the preparation process does not involve the crystal form transformation of the drug, the high stability of the crystalline cefditoren pivoxil can be maintained, and the stability risk during storage is reduced.

[0039] Since cefditoren pivoxil has low solubility, it is not conducive to oral preparations, but after being prepared into a self-microemulsion drug delivery system, the solubility of cefditoren pivoxil can be improved, and the bitterness can be reduced, and then the cefditoren pivoxil self-microemulsion drug delivery system is mixed with pharmaceutically acceptable excipients for granulation, the obtained cefditoren pivoxil granules have good taste, particle size distribution, dissolution release rate and stability, the preparation method is simple, the process reproducibility is good, and the production can be scaled up.

[0040] The present application adopts a novel oral administration system, i.e., a self-emulsifying administration system, can better solve the solubility problem of the poorly soluble drug cefditoren pivoxil, and the prepared cefditoren pivoxil granules have good dissolution release rate, and make a positive contribution to improving the oral bioavailability of the drug. In addition, the prepared cefditoren pivoxil granules have uniform particle size distribution, good taste, content, content uniformity and preparation stability.

[0041] The preparation method of the present application is simple, the process reproducibility is good, and the production can be scaled up. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 The present application is an embodiment of the present application, and the present application is an embodiment of the present application. DETAILED DESCRIPTION

[0043] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0044] Example 1

[0045] The preparation method of the cefditoren pivoxil granule preparation comprises the following steps:

[0046] (1) Weigh each raw material; prepare cefditoren pivoxil granule preparation (500 bags) according to the ratio in Table 1 below, and the content of active ingredient in the granules is 50mg / bag in terms of cefditoren.

[0047] The content of cefditoren pivoxil and cefditoren is converted according to the corresponding molecular weight with a coefficient of 0.8161 (W1 / W2), wherein W1 is the molecular weight of cefditoren 506.58, and W2 is the molecular weight of cefditoren 620.72.

[0048] Table 1 Prescription composition of Example 1

[0049]

[0050] The cefditoren pivoxil self-microemulsion administration system includes a cefditoren pivoxil self-microemulsion administration system solution and a solid carrier, and the mass ratio of the cefditoren pivoxil self-microemulsion administration system solution to the solid carrier is 2:1.

[0051] The cefditoren pivoxil self-microemulsion administration system solution includes cefditoren pivoxil and a blank self-microemulsion administration system solution, and the mass ratio of cefditoren pivoxil to the blank self-microemulsion administration system solution is 1:5.

[0052] The blank self-microemulsifying drug delivery system solution comprises an oil phase, an emulsifier and a co-emulsifier, the mass ratio of the emulsifier to the co-emulsifier is 1:1, and the weight ratio of the oil phase to the mixture of the emulsifier and the co-emulsifier is 3:2.

[0053] (2) Preparation of the blank self-microemulsifying drug delivery system solution: the oil phase, the emulsifier and the co-emulsifier are mixed and stirred at a stirring speed of 250 rpm for 1 h to obtain the blank self-microemulsifying drug delivery system solution;

[0054] (3) Preparation of the cefditoren pivoxil self-microemulsifying drug delivery system solution: cefditoren pivoxil is added to the blank self-microemulsifying drug delivery system solution obtained in step (2), and homogenization is performed by using a homogenizing emulsifier at a homogenization speed of 6000 rpm for 1 h to obtain the cefditoren pivoxil self-microemulsifying drug delivery system solution;

[0055] (4) Preparation of the cefditoren pivoxil self-microemulsifying drug delivery system: a solid carrier is dissolved in water to obtain a solid carrier solution, and the mass fraction of the solid carrier in the solid carrier solution is 5%; the cefditoren pivoxil self-microemulsifying drug delivery system solution obtained in step (3) is slowly added to the solid carrier solution, the feeding speed is 10% per minute based on the total mass of the cefditoren pivoxil self-microemulsifying drug delivery system solution being 100%, homogenization is performed by using a homogenizing emulsifier at a homogenization speed of 9000 rpm for 1 h, ultrasonic treatment is performed at a power of 150 W for 15 min, and freeze-drying is performed at a temperature of -40 °C for 24 h to obtain the cefditoren pivoxil self-microemulsifying drug delivery system;

[0056] (5) A binder is dissolved in water to obtain a binder solution, and the mass fraction of the binder in the binder solution is 6%; a flavoring agent is added to the binder solution to obtain a mixed solution;

[0057] (6) The cefditoren pivoxil self-microemulsifying drug delivery system obtained in step (4), a bulking agent, a disintegrating agent, a sweetening agent and a thickening agent are premixed in a wet granulator, the rotating speed of the wet granulator is 200 rpm, the cutting speed is 1500 rpm, and the premixing time is 5 min to obtain a premixing product;

[0058] (7) The premixing product is transferred to a centrifugal granulator, the mixed solution obtained in step (5) is sprayed into the centrifugal granulator to granulate, the atomization pressure of the centrifugal granulator is 0.3 MPa, the rotating speed of the main machine is 13000 rpm, the rotating speed of the slurry pump is 20 rpm, the granulating time is 1 min, drying is performed to control the water content of the granules to be less than 1.5%, screening is performed to discard the granules with a particle size greater than 850 μm, the screened granules are transferred to a mixer, an aromatic agent is further added and mixed, the rotating speed of the mixer is 10 rpm, and the mixing time is 5 min to obtain the cefditoren pivoxil granular preparation.

[0059] (8) The cefditoren pivoxil granule preparation is packaged with paper / aluminum / polyethylene pharmaceutical composite film to obtain the product.

[0060] Example 2

[0061] The difference between the prescription of this example and Example 1 is that the oil phase is hydrogenated vegetable oil.

[0062] Cefditoren pivoxil granules (500 bags) are prepared according to the proportions in Table 2 below, with the active ingredient content being 50 mg / bag of cefditoren in the granules.

[0063] Table 2 Prescription composition of Example 2

[0064]

[0065] The mass ratio of emulsifier to co-emulsifier in the above table is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 3:2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:5, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 2:1.

[0066] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0067] Example 3

[0068] The difference between the prescription of this example and Example 1 is that the oil phase is ethyl oleate.

[0069] Cefditoren pivoxil granules (500 bags) are prepared according to the proportions in Table 3 below, with the active ingredient content being 50 mg / bag of cefditoren in the granules.

[0070] Table 3 Prescription composition of Example 3

[0071]

[0072] The mass ratio of emulsifier to co-emulsifier in the above table is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 3:2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:5, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 2:1.

[0073] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0074] Example 4

[0075] The difference between the prescription of this example and Example 1 is that the emulsifier is sodium dodecyl sulfate.

[0076] Cefditoren pivoxil granules (500 bags) were prepared according to the following Table 4, and the active ingredient was contained in the granules at a content of 50 mg / bag in terms of cefditoren.

[0077] Table 4 Prescription composition of Example 4

[0078]

[0079]

[0080] The mass ratio of the emulsifier to the co-emulsifier in the above table was 1:1, the mass ratio of the oil phase to the mixture of the emulsifier and the co-emulsifier was 3:2, the mass ratio of cefditoren pivoxil to the blank self-microemulsifying drug delivery system solution was 1:5, and the mass ratio of the cefditoren pivoxil self-microemulsifying drug delivery system solution to the solid carrier was 2:1.

[0081] The preparation method and parameters of steps (2)-(8) in this example were the same as those of Example 1.

[0082] Example 5

[0083] The prescription of this example was different from that of Example 1 in that the co-emulsifier was ethanol.

[0084] Cefditoren pivoxil granules (500 bags) were prepared according to the following Table 5, and the active ingredient was contained in the granules at a content of 50 mg / bag in terms of cefditoren.

[0085] Table 5 Prescription composition of Example 5

[0086]

[0087] The mass ratio of the emulsifier to the co-emulsifier in the above table was 1:1, the mass ratio of the oil phase to the mixture of the emulsifier and the co-emulsifier was 3:2, the mass ratio of cefditoren pivoxil to the blank self-microemulsifying drug delivery system solution was 1:5, and the mass ratio of the cefditoren pivoxil self-microemulsifying drug delivery system solution to the solid carrier was 2:1.

[0088] The preparation method and parameters of steps (2)-(8) in this example were the same as those of Example 1.

[0089] Example 6

[0090] The prescription of this example was different from that of Example 1 in that the co-emulsifier was polyethylene glycol 400.

[0091] Cefditoren pivoxil granules (500 bags) were prepared according to the following Table 6, and the active ingredient was contained in the granules at a content of 50 mg / bag in terms of cefditoren.

[0092] Table 6 Prescription composition of Example 6

[0093]

[0094] The mass ratio of emulsifier to co-emulsifier is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 3:2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:5, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 2:1.

[0095] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0096] Example 7

[0097] The prescription of this example is different from that of Example 1 in that the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 2:3.

[0098] Cefditoren pivoxil granules (500 bags) were prepared according to the proportions in Table 7 below, and the content of active ingredient, cefditoren, in the granules was 50 mg / bag.

[0099] Table 7 Prescription composition of Example 7

[0100]

[0101]

[0102] The mass ratio of emulsifier to co-emulsifier is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 2:3, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:5, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 2:1.

[0103] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0104] Example 8

[0105] The prescription of this example is different from that of Example 1 in that the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 4:1.

[0106] Cefditoren pivoxil granules (500 bags) were prepared according to the proportions in Table 8 below, and the content of active ingredient, cefditoren, in the granules was 50 mg / bag.

[0107] Table 8 Prescription composition of Example 8

[0108]

[0109] The mass ratio of emulsifier to co-emulsifier is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 4:1, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:5, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 2:1.

[0110] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0111] Example 9

[0112] The prescription of this example is different from that of Example 1 in that the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:2.

[0113] Cefditoren pivoxil granules (500 bags) were prepared according to the proportions in Table 9 below, and the content of active ingredient, calculated as cefditoren, in the granules was 50 mg / bag.

[0114] Table 9 Prescription composition of Example 9

[0115]

[0116] The mass ratio of emulsifier to co-emulsifier is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 3:2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:2, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 2:1.

[0117] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0118] Example 10

[0119] The prescription of this example is different from that of Example 1 in that the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:10.

[0120] Cefditoren pivoxil granules (500 bags) were prepared according to the proportions in Table 10 below, and the content of active ingredient, calculated as cefditoren, in the granules was 50 mg / bag.

[0121] Table 10 Prescription composition of Example 10

[0122]

[0123]

[0124] The mass ratio of emulsifier to co-emulsifier is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 3:2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:10, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 2:1.

[0125] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0126] Example 11

[0127] The prescription of this example is different from that of Example 1 in that the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 5:1.

[0128] Cefditoren pivoxil granules (500 bags) were prepared according to the proportions in Table 11, and the content of active ingredient, cefditoren, in the granules was 50 mg / bag.

[0129] Table 11 Prescription composition of Example 11

[0130]

[0131] The mass ratio of emulsifier to co-emulsifier is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 3:2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:5, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 5:1.

[0132] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0133] Example 12

[0134] The prescription of this example is different from that of Example 1 in that the sweetener used is aspartame.

[0135] Cefditoren pivoxil granules (500 bags) were prepared according to the proportions in Table 12, and the content of active ingredient, cefditoren, in the granules was 50 mg / bag.

[0136] Table 12 Prescription composition of Example 12

[0137]

[0138] The preparation method and parameters of steps (2)-(8) of this example are the same as those of Example 1.

[0139] Example 13

[0140] The prescription of this example is different from that of Example 1 in that the amount of disintegrant is 3.0 g, and the amount of filler is 201.2 g.

[0141] Cefditoren pivoxil granules (500 bags) were prepared according to the formulation in Table 13 below, with the active ingredient having a content of 50 mg / bag of cefditoren in the granules.

[0142] Table 13 Formulation of Example 1

[0143]

[0144] The preparation method and parameters of steps (2) to (8) of this example were the same as those of Example 1.

[0145] Comparative Example 1

[0146] The prescription of this example was different from that of Example 1 in that the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution was 1:1.

[0147] Cefditoren pivoxil granules (500 bags) were prepared according to the formulation in Table 14 below, with the active ingredient having a content of 50 mg / bag of cefditoren in the granules.

[0148] Table 14 Formulation of Comparative Example 1

[0149]

[0150] In the above table, the mass ratio of emulsifier to co-emulsifier was 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier was 3:2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution was 1:1, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier was 2:1.

[0151] The preparation method and parameters of steps (2) to (8) of this example were the same as those of Example 1.

[0152] Comparative Example 2

[0153] The prescription of this example was different from that of Example 1 in that the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution was 1:11.

[0154] Cefditoren pivoxil granules (500 bags) were prepared according to the formulation in Table 15 below, with the active ingredient having a content of 50 mg / bag of cefditoren in the granules.

[0155] Table 15 Formulation of Comparative Example 2

[0156]

[0157]

[0158] The mass ratio of emulsifier to co-emulsifier in the above table is 1:1, the mass ratio of oil phase to the mixture of emulsifier and co-emulsifier is 3:2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:11, and the mass ratio of cefditoren pivoxil self-microemulsifying drug delivery system solution to solid carrier is 2:1.

[0159] The preparation method and parameters of steps (2)-(8) in this example are the same as those in Example 1.

[0160] Comparative Example 3

[0161] The prescription of this comparative example is different from that of Example 1 in that this comparative example does not contain oil phase, emulsifier, co-emulsifier, and solid carrier.

[0162] Cefditoren pivoxil granules (500 bags) were prepared according to the proportions in Table 16 below, and the content of active ingredient, cefditoren, in the granules was 50 mg / bag.

[0163] Table 16 Prescription composition of Comparative Example 3

[0164]

[0165] The preparation method of this comparative example is different from that of Example 1 in that this comparative example uses cefditoren pivoxil as the raw material for granule preparation, and does not need to prepare cefditoren pivoxil self-microemulsifying drug delivery system.

[0166] The preparation process of this comparative example is as follows:

[0167] (1) Each raw material was weighed according to the proportions in Table 16;

[0168] (2) The binder was dissolved in water to obtain a binder solution, and the mass fraction of the binder in the binder solution was 6%. The flavoring agent was added to the binder solution to obtain a mixed solution;

[0169] (3) Cefditoren pivoxil, filler, disintegrant, sweetener, and thickening agent were pre-mixed in a wet granulator, the rotation speed of the wet granulator was 200 rpm, the cutting rotation speed was 1500 rpm, and the pre-mixing time was 5 min to obtain a pre-mixed product;

[0170] (4) The obtained pre-mixed product was transferred to a centrifugal granulator, and the mixed solution obtained in step (2) was sprayed to granulate with water as a wetting agent. The atomization pressure of the centrifugal granulator was 0.3 MPa, the main machine rotation speed was 13000 rpm, the spraying pump rotation speed was 20 rpm, the granulation time was 1 min, and the granules were dried to control the moisture content to be less than 1.5%. The granules were screened, and the granules with a particle size greater than 850 μm were discarded. The screened granules were mixed in a mixer, and the flavoring agent was added for mixing. The mixing rotation speed of the mixer was 10 rpm, and the mixing time was 5 min to obtain cefditoren pivoxil granule preparation.

[0171] (5) The cefditoren pivoxil granule preparation is packaged with paper / aluminum / polyethylene pharmaceutical composite film to obtain the product.

[0172] Comparative Example 4

[0173] The prescription of this comparative example is the same as that of Example 1.

[0174] Cefditoren pivoxil granules (500 bags) are prepared according to the proportions in Table 17 below, with the active ingredient content being 50 mg / bag of cefditoren in the granules.

[0175] Table 17 Prescription composition of Comparative Example 4

[0176]

[0177] The difference between this comparative example and the preparation method of Example 1 is that the preparation method of the cefditoren pivoxil self-microemulsifying drug delivery system granules in this comparative example uses a wet granulation process.

[0178] The preparation process of this comparative example is as follows:

[0179] (1) The raw materials are weighed according to the proportions in Table 17;

[0180] (2) Preparation of blank self-microemulsifying drug delivery system solution: the oil phase, emulsifier and co-emulsifier are mixed and stirred at a stirring speed of 250 rpm for 1 h to obtain a blank self-microemulsifying drug delivery system solution;

[0181] (3) Preparation of cefditoren pivoxil self-microemulsifying drug delivery system solution: cefditoren pivoxil is added to the blank self-microemulsifying drug delivery system solution obtained in step (2), and homogenized using a homogenizing emulsifier at a homogenizing speed of 6000 rpm for 1 h to obtain a cefditoren pivoxil self-microemulsifying drug delivery system solution;

[0182] (4) Preparation of cefditoren pivoxil self-microemulsifying drug delivery system: the solid carrier is dissolved in water to obtain a solid carrier solution, and the mass fraction of the solid carrier in the solid carrier solution is 2% to 12%; the cefditoren pivoxil self-microemulsifying drug delivery system solution obtained in step (3) is slowly added to the solid carrier solution, and the addition speed is 10% per minute based on the total mass of the cefditoren pivoxil self-microemulsifying drug delivery system solution being 100%; the homogenizing emulsifier is used for homogenization at a homogenizing speed of 9000 rpm for 1 h; ultrasonic treatment is performed at an ultrasonic power of 150 W for 15 min; and freeze-drying is performed at a temperature of -40°C for 24 h to obtain a cefditoren pivoxil self-microemulsifying drug delivery system;

[0183] (5) dissolving the adhesive with water to obtain an adhesive solution, the mass fraction of the adhesive in the adhesive solution is 6%, adding the flavoring agent into the adhesive solution to disperse to obtain a mixed solution;

[0184] (6) adding the cefditoren pivoxil self-microemulsion drug delivery system, the filler, the disintegrant, the sweetening agent and the thickening agent obtained in step (4) into a wet granulator for premixing, the rotating speed of the wet granulator is 200 rpm, the cutting rotating speed is 1500 rpm, the premixing time is 5 min, then adding the mixed solution obtained in step (5) to granulate for 1 min with water as the wetting agent, the rotating speed of the wet granulator is 300 rpm, the cutting rotating speed is 1800 rpm, and the wet granulator is subjected to wet granulation by a shaking granulator;

[0185] (7) after the fluidized bed drying to the granules with the water content less than 1.5%, the dry granulation is performed by a rapid granulator;

[0186] (8) after the granulation, the granules are put into a square-cone mixer, and the flavoring agent is added for mixing for 5 min, the mixing rotating speed is 10 rpm, to obtain the cefditoren pivoxil granule preparation;

[0187] (9) the cefditoren pivoxil granule preparation is packaged by using a paper / aluminum / polyethylene composite film for medicine, to obtain the product.

[0188] Comparative Example 5

[0189] The prescription of the present comparative example is the same as that of Example 1.

[0190] The cefditoren pivoxil granules (500 bags) are prepared according to the proportion in Table 18 below, and the content of the active ingredient, cefditoren, in the granules is 50 mg / bag.

[0191] Table 18 Prescription composition of Comparative Example 5

[0192]

[0193] The difference between the preparation method of the present comparative example and that of Example 1 is that the preparation process of the cefditoren pivoxil self-microemulsion drug delivery system in step (4) is different, and no ultrasonic treatment is performed.

[0194] The preparation process of the present comparative example is as follows:

[0195] (1) each raw material is weighed according to the proportion in Table 18;

[0196] (2) blank self-microemulsion drug delivery system solution preparation: the oil phase, the emulsifier and the co-emulsifier are mixed and stirred, the stirring rotating speed is 250 rpm, and the stirring time is 1 h, to obtain the blank self-microemulsion drug delivery system solution;

[0197] (3) Cefditoren pivoxil self-microemulsifying drug delivery system solution preparation: Cefditoren pivoxil was added to the blank self-microemulsifying drug delivery system solution obtained in step (2), and homogenized by using a homogenizer at a speed of 6000 rpm for 1 h to obtain a cefditoren pivoxil self-microemulsifying drug delivery system solution;

[0198] (4) Cefditoren pivoxil self-microemulsifying drug delivery system preparation: solid carriers were dissolved in water to obtain a solid carrier solution, and the mass fraction of the solid carrier in the solid carrier solution was 2% to 12%; the cefditoren pivoxil self-microemulsifying drug delivery system solution obtained in step (3) was slowly added to the solid carrier solution, and the feeding speed was 10% per minute based on the total mass of the cefditoren pivoxil self-microemulsifying drug delivery system solution, which was homogenized by using a homogenizer at a speed of 9000 rpm for 1 h, and then freeze-dried at a temperature of -40 °C for 24 h to obtain a cefditoren pivoxil self-microemulsifying drug delivery system;

[0199] (5) A binder solution was obtained by dissolving a binder in water, and the mass fraction of the binder in the binder solution was 6%; a flavoring agent was added to the binder solution to obtain a mixed solution;

[0200] (6) The cefditoren pivoxil self-microemulsifying drug delivery system obtained in step (4), a filler, a disintegrant, a sweetening agent, and a thickening agent were pre-mixed in a wet granulator at a speed of 200 rpm, a cutting speed of 1500 rpm, and a pre-mixing time of 5 min to obtain a pre-mixed product;

[0201] (7) The pre-mixed product was transferred to a centrifugal granulator, and the mixed solution obtained in step (5) was sprayed into the centrifugal granulator to granulate with water as a wetting agent, the atomization pressure of the centrifugal granulator was 0.3 MPa, the main machine speed was 13000 rpm, the spraying pump speed was 20 rpm, the granulation time was 1 min, and then the granules were dried by controlling the water content to be less than 1.5%, screened, and the particles with a particle size greater than 850 μm were discarded, and then the particles were mixed in a mixer, and a fragrance was added for mixing, the mixing speed of the mixer was 10 rpm, and the mixing time was 5 min to obtain a cefditoren pivoxil granular preparation.

[0202] (8) The cefditoren pivoxil granular preparation was packaged by using a paper / aluminum / polyethylene pharmaceutical composite film to obtain the product.

[0203] Comparative Example 6

[0204] The blank self-microemulsifying drug delivery system solution of this comparative example was prepared according to the same prescription as the blank self-microemulsifying drug delivery system solution of Example 1. The difference is that the ratio of the emulsifier to the co-emulsifier in this comparative example is 1:6.

[0205] Table 19 Prescription composition of Comparative Example 6

[0206]

[0207] Comparative Example 7

[0208] This comparative example is a blank self-microemulsifying drug delivery system solution prepared with the same prescription as the blank self-microemulsifying drug delivery system solution of Example 1. The difference is that the ratio of emulsifier to co-emulsifier in this comparative example is 6:1.

[0209] Table 20 Prescription composition of Comparative Example 7

[0210]

[0211] Comparative Example 8

[0212] This comparative example is a blank self-microemulsifying drug delivery system solution prepared with the same prescription as the blank self-microemulsifying drug delivery system solution of Example 1. The difference is that the ratio of emulsifier to co-emulsifier in this comparative example is 6:1.

[0213] Table 21 Prescription composition of Comparative Example 8

[0214]

[0215] Comparative Example 9

[0216] This comparative example is a blank self-microemulsifying drug delivery system solution prepared with the same prescription as the blank self-microemulsifying drug delivery system solution of Example 1. The difference is that the ratio of emulsifier to co-emulsifier in this comparative example is 6:1.

[0217] Table 22 Prescription composition of Comparative Example 9

[0218]

[0219] Test Example 1 Emulsification effect of blank self-microemulsifying drug delivery system solution

[0220] The emulsification effects of the blank self-microemulsifying drug delivery systems obtained in Examples 1 to 11 and Comparative Examples 6 to 9 were evaluated in terms of self-emulsification time and emulsification degree, and the results were as follows:

[0221] Table 23 Emulsification effect

[0222]

[0223]

[0224] The results show that the blank self-microemulsifying drug delivery systems obtained in Examples 1 to 8 have good emulsification effect; in Comparative Example 6, due to insufficient proportion of emulsifier, stable micelle structure cannot be formed, resulting in prolonged emulsification time, and although the co-emulsifier can assist emulsification, it cannot completely replace the role of the emulsifier, resulting in delamination; in Comparative Example 7, due to low proportion of co-emulsifier, the interfacial tension is insufficiently reduced, resulting in prolonged self-emulsification time, and the formed microemulsion particles have large particle size and turbid appearance; in Comparative Example 8, the proportion of oil phase is too high, and the emulsifier cannot sufficiently cover the surface of oil droplets, resulting in insufficient reduction of interfacial tension, so the emulsification time is prolonged; in Comparative Example 9, the proportion of oil phase is too low, and the emulsifier cannot form enough micelles to wrap the oil droplets, resulting in long emulsification time and failure to form uniform microemulsion.

[0225] Solution stability of blank self-microemulsifying drug delivery system in Test Example 2

[0226] The solutions of the blank self-microemulsifying drug delivery systems obtained in Examples 1 to 11 were subjected to physical stability research, and the appearance state was recorded after standing for 24 h, centrifugation at 3000 rpm for 15 min, and temperature cycling experiment (switching every 24 h) at 5°C / 40°C. The results are as follows:

[0227] Table 24 Physical stability research of solution of blank self-microemulsifying drug delivery system

[0228]

[0229] The results show that the blank self-microemulsifying drug delivery systems in Examples 1 to 11 have good physical stability, and the appearance state does not change under the conditions of standing for 24 h, centrifugation for 15 min, and 6 cycles of temperature cycling experiment.

[0230] Particle size detection results of cefditoren pivoxil self-microemulsifying drug delivery system in Test Example 3

[0231] The cefditoren pivoxil self-microemulsifying drug delivery systems obtained after lyophilization of Examples 1 to 11 and Comparative Examples 1 / 2 / 5 were redispersed in water medium, and the particle size was detected by dynamic light scattering method, and the particle size stability after standing for different time was investigated. The results are as follows:

[0232] Table 25 Particle size detection results of cefditoren pivoxil self-microemulsifying drug delivery system

[0233]

[0234]

[0235] The results show that: the cefditoren pivoxil self-microemulsifying drug delivery systems prepared in Examples 1 to 11 and Comparative Example 1 / 2 / 5 are all in nanoscale. The particle size stability results of Examples 1 to 11 are good within 24 hours of standing, the polydispersity index (PDI) is less than 0.3, and the particle size distribution is uniform; the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution in Comparative Example 1 is 1:1, the particle size of the cefditoren pivoxil self-microemulsifying drug delivery system prepared is large, and the dispersibility is poor, and it is obviously aggregated during standing; the particle size of the cefditoren pivoxil self-microemulsifying drug delivery system prepared in Comparative Example 3 without ultrasonic treatment is large, and the particle size and PDI value both increase during standing, indicating that there is a risk of aggregation.

[0236] Test Example 4 Encapsulation efficiency and drug loading rate

[0237] The encapsulation efficiency (EE) and drug loading rate (DL) of the cefditoren pivoxil self-microemulsifying drug delivery systems prepared in Examples 1 to 11 and Comparative Examples 1 to 2 were determined (n = 3) respectively to evaluate the effective packaging ratio of the drug and the drug loading capacity of the system, and the results are as follows:

[0238] Table 26 Encapsulation efficiency and drug loading rate detection results of cefditoren pivoxil self-microemulsifying drug delivery system

[0239]

[0240]

[0241] The results show that: the cefditoren pivoxil self-microemulsifying drug delivery systems prepared in Examples 1 to 11 and Comparative Example 1 have high encapsulation efficiency and drug loading rate, and the drug loading rate of the cefditoren pivoxil self-microemulsifying drug delivery system prepared in Comparative Example 2 is low due to the large proportion of excipients.

[0242] Test Example 5 Dissolution curve detection

[0243] The cefditoren pivoxil granules prepared in Examples 1 to 13 and Comparative Examples 1 to 5 were compared with the imported cefditoren pivoxil granule reference preparation (trade name: Meiji, specification: 50mg (potency) / bag, certificate holder: Meiji Seika Pharma Co., Ltd.) in vitro dissolution, using the dissolution and release determination method (second method in Chinese Pharmacopoeia 2020 Edition Volume IV 0931), 900mL, pH4.5 acetate solution as the dissolution medium, the rotation speed was 50rpm, and the operation was carried out according to the law. At 5, 10, 15, 30, 45, 60, 90, 120, 180min, 10mL of sample was taken, the dissolution amount of each bag was calculated by ultraviolet spectrophotometry, and the detection wavelength was 272nm. The prepared cefditoren pivoxil granules and the reference preparation were compared for dissolution curve similarity, and f2 was greater than 50, indicating that the dissolution curves were similar under the dissolution conditions.

[0244] Table 27 Dissolution curve results of examples 1-13 and comparative examples 1-5 and reference preparation

[0245] Time (min) 5 10 15 30 45 60 90 120 180 f2 Example 1 61 64 67 70 71 73 75 76 78 77 Example 2 55 58 61 65 68 71 73 75 79 72 Example 3 53 56 61 64 67 69 70 72 75 70 Example 4 53 55 59 62 65 67 68 69 70 63 Example 5 58 62 66 70 72 75 77 79 81 68 Example 6 61 65 67 69 72 74 76 79 82 68 Example 7 53 56 59 63 65 68 71 71 73 67 Example 8 50 53 57 60 63 66 68 70 72 58 Example 9 48 50 53 58 62 65 67 69 72 53 Example 10 64 68 70 73 76 79 81 81 85 53 Example 11 52 54 56 59 62 65 67 69 71 58 Example 12 60 64 67 70 72 73 75 77 79 74 Example 13 54 56 58 62 65 68 70 72 75 66 Comparative Example 1 45 48 50 53 55 58 60 63 66 44 Comparative Example 2 65 70 73 78 82 86 89 93 96 49 Comparative Example 3 6 8 10 14 16 18 21 24 28 14 Comparative Example 4 41 49 54 59 64 67 69 72 75 51 Comparative Example 5 50 53 55 57 61 63 63 65 66 52 Reference Formulation 60 63 65 68 69 70 72 72 74 /

[0246] The results show that: examples 1 to 13, by preparing cefditoren pivoxil self-microemulsifying drug delivery system, the dissolution curve can be fitted with the reference preparation; comparative example 1, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:1, the prepared cefditoren pivoxil granules are dissolved slowly, and do not fit with the reference; comparative example 2, the mass ratio of cefditoren pivoxil to blank self-microemulsifying drug delivery system solution is 1:11, the prepared cefditoren pivoxil granules are dissolved quickly, and do not fit with the reference; comparative example 3, the sample is prepared directly using the raw material drug, the dissolution is low, and does not fit with the reference preparation; comparative example 4, the granules are prepared using the wet granulation process, and the dissolution curve does not fit well with the reference preparation; comparative example 5, the cefditoren pivoxil self-microemulsifying drug delivery system is prepared without ultrasonic treatment, and the dissolution curve does not fit well with the reference preparation.

[0247] Test example 6 stability evaluation

[0248] The cefditoren pivoxil granules obtained from examples 1 to 13 and comparative examples 3 to 5, and the imported cefditoren pivoxil granules reference preparation (trade name is Meilaike, specification is 50mg (potency) / bag, and the certificate holder is Meiji Seika Pharma Co., Ltd.) were subjected to stability investigation under accelerated conditions (40℃±2℃, 75%±5%RH), and were placed for 6 months, and the stability results are as follows:

[0249] Table 28 Stability results of examples 1-13 and comparative examples 3-5 and reference preparation

[0250]

[0251]

[0252] The results show that: the stability of each example and comparative example is not inferior to or even better than the reference preparation, which indicates that the prescription composition and preparation process of the application are beneficial to the stability of the preparation.

[0253] The above only describes the preferred embodiments of the present application, but the protection scope of the present application is not limited thereto, and any modification and replacement based on the technical solutions and inventive concepts provided by the present application should be covered within the protection scope of the present application.

Claims

1. A cefditoren pivoxil granular preparation, characterized by, The granular preparation of cefditoren pivoxil comprises the following raw materials by weight: cefditoren pivoxil self-microemulsion drug delivery system 50-60 parts, filler 30-50 parts, disintegrant 0.5-3 parts, binder 0.1-2 parts, sweetener 1-7 parts, flavoring agent 0.1-2 parts, thickening agent 0.1-2 parts, and fragrance 0.01-0.05 parts; The cefditoren pivoxil self-microemulsion drug delivery system comprises a cefditoren pivoxil self-microemulsion drug delivery system solution and a solid carrier, and the mass ratio of the cefditoren pivoxil self-microemulsion drug delivery system solution to the solid carrier is (1-10):1; The cefditoren pivoxil self-microemulsion drug delivery system solution comprises cefditoren pivoxil and a blank self-microemulsion drug delivery system solution, and the mass ratio of cefditoren pivoxil to the blank self-microemulsion drug delivery system solution is 1:(2-10); The blank self-microemulsion drug delivery system solution comprises an oil phase, an emulsifier and a co-emulsifier, the mass ratio of the emulsifier to the co-emulsifier is (1-5):(1-5), and the weight ratio of the oil phase to the mixture of the emulsifier and the co-emulsifier is (1-5):(1-5).

2. The cefditoren pivoxil granular preparation according to claim 1, wherein The oil phase is one or a mixture of several of monoglyceride oleic acid, monoglyceride linoleic acid, ethyl oleate or hydrogenated vegetable oil; The emulsifier is one or a mixture of several of fatty acid sorbitan, Tween 80, sodium dodecyl sulfate or Span 80; The co-emulsifier is one or a mixture of several of ethanol, butanol, glycerol, diethylene glycol monoethyl ether or polyethylene glycol 400; The solid carrier is one or a mixture of several of sucrose, mannitol, lactose, glucose or trehalose.

3. The cefditoren pivoxil granular preparation according to claim 1, wherein The filler is one or a mixture of several of microcrystalline cellulose, sucrose, lactose or mannitol; The disintegrant is one or a mixture of several of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked povidone or cross-linked sodium carboxymethyl cellulose; The binder is one or a mixture of several of hypromellose, povidone or hydroxypropyl cellulose; The sweetener is one or a mixture of several of aspartame, sucralose or sodium saccharin; The flavoring agent is one or a mixture of several of sodium chloride, β-cyclodextrin, ion exchange resin or chitosan; The thickening agent is one or a mixture of several of sodium carboxymethyl cellulose, polyoxyethylene, dextrin, gelatin or gum arabic; The fragrance is one or a mixture of several of vanillin, ethyl vanillin, strawberry flavor or cherry flavor.

4. A method for preparing a cefditoren pivoxil granular formulation, characterized by, The method comprises the following steps: (1) The granular preparation of cefditoren pivoxil is prepared according to any one of claims 1-3; (2) The blank self-microemulsion drug delivery system solution is prepared by mixing and stirring the oil phase, the emulsifier and the co-emulsifier; (3) The cefditoren pivoxil self-microemulsion drug delivery system solution is prepared by adding cefditoren pivoxil into the blank self-microemulsion drug delivery system solution obtained in step (2) and homogenizing with a homogenizing emulsifier. (4) Cefditoren pivoxil self-microemulsion drug delivery system is prepared by dissolving the solid carrier in water to obtain a solid carrier solution, slowly adding the cefditoren pivoxil self-microemulsion drug delivery system solution obtained in step (3) into the solid carrier solution, homogenizing with a homogenizer, ultrasonic treatment, and freeze-drying to obtain the cefditoren pivoxil self-microemulsion drug delivery system; (5) The adhesive is dissolved in water to obtain an adhesive solution, and the flavoring agent is added into the adhesive solution to obtain a mixed solution; (6) The cefditoren pivoxil self-microemulsion drug delivery system obtained in step (4), the filler, the disintegrant, the sweetening agent, and the thickening agent are premixed in a wet granulator to obtain a premixed product; (7) The premixed product is transferred to a centrifugal granulator, the mixed solution obtained in step (5) is sprayed, water is used as a wetting agent for granulation, drying is performed, the water content of the granules is controlled to be less than 1.5%, the granules with a particle size greater than 850 μm are removed, and the granules after screening are mixed in a mixer and then the fragrance is added to obtain the cefditoren pivoxil granule preparation.

5. The process for preparing cefditoren pivoxil granules according to claim 4, wherein In step (2), the stirring speed is 100-400 rpm, and the stirring time is 0.5-2 h.

6. The process for the preparation of granules of cefditoren pivoxil according to claim 4, characterized in that, In step (3), the homogenization speed is 800-10000 rpm, and the homogenization time is 0.5-2 h.

7. The process for preparing cefditoren pivoxil granules according to claim 4, wherein In step (4), the mass fraction of the solid carrier in the solid carrier solution is 2%-12%, the feeding speed of the cefditoren pivoxil self-microemulsion drug delivery system solution slowly added into the solid carrier solution is 5%-20% / min based on the total mass of the cefditoren pivoxil self-microemulsion drug delivery system solution being 100%, the homogenization speed is 800-10000 rpm, the homogenization time is 0.5-2 h, the ultrasonic power is 100-300 W, the ultrasonic time is 10-30 min, and the freeze-drying temperature is -40℃±10℃, and the freeze-drying time is 12-36 h.

8. The process for preparing cefditoren pivoxil granules according to claim 4, wherein In step (5), the mass fraction of the adhesive in the adhesive solution is 4%-8%.

9. The process for preparing cefditoren pivoxil granules according to claim 4, wherein In step (6), the rotation speed of the wet granulator is 110-300 rpm, the cutting speed is 1000-2100 rpm, and the premixing time is 5-10 min.

10. The process for the preparation of granules of cefditoren pivoxil according to claim 4, characterized in that, In step (7), the atomization pressure of the centrifugal granulator is 0.1-0.5 MPa, the rotation speed of the main machine is 8000-15000 rpm, the rotation speed of the slurry pump is 10-30 rpm, the granulation time is 0.5-1.5 min, the mixing speed of the mixer is 10-15 rpm, and the mixing time is 3-8 min.

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